gc-1-compound and Obesity

The article is principally intended to describe the recent evolutions in the field of research concerned with the metabolic actions of thyroid hormones and those of some of their metabolites or derivatives. Mitochondria, as a result of their functions, represent the principal objective of scientists investigating the mechanisms underlying the effects of thyroid hormones or their metabolites/derivatives.. Indeed, some important recent findings concern these organelles, and in particular mitochondrial uncoupling and its modulation by effectors. Traditionally, thyroxine (T4) and tri-iodo-L-thyronine (T3) were the only thyroid hormones considered to have metabolic effects, and they alone were considered for potential as agents that might counteract some important abnormalities such as dyslipidaemias and obesity. Several observations, however, led to a reconsideration of this idea. In recent years, studies dealing with the biological activities of some natural metabolites or structural analogues of thyroid hormones have revealed abilities to ameliorate some major worldwide medical problems, such as artherosclerosis, obesity and cardiovascular diseases. Among natural metabolites, 3,5-diiodothyronine (T2) has been shown to powerfully reduce adiposity and dyslipidaemia and to reverse hepatic steatosis without unfavourable side-effects usually observed when T3 or T4 is used. Examples of synthetic analogues are GC-1 (or sobetirome) and KB2115 (or eprotirome) which show ipolipidaemic and antiaterogenic capacities. Clinical trials are in progress for these last agents.. In view of the above-mentioned actions, some of these compounds are now undergoing clinical trials and may have important implications for clinical practice or researches in the field of both endocrinology and metabolic-related abnormalities such as diabetes and dyslipidaemias.

Topics: Acetates; Adiposity; Anilides; Animals; Atherosclerosis; Cardiovascular Diseases; Clinical Trials as Topic; Diiodothyronines; Dyslipidemias; Energy Metabolism; Fatty Liver; Humans; Lipid Metabolism; Mice; Mitochondria; Obesity; Phenols; Rats; Thyroid Hormones

With nearly 40% of U.S. adults obese, and childhood and adolescent rates rising, obesity and associated comorbidities are serious public health concerns with massive societal costs. Often, lifestyle interventions do not offer sufficient weight loss to improve health, requiring surgery and medications as adjunct management strategies. Here, we present a 4-month case study in which the sustained, low-dose, and constant administration of the thyroid receptor β selective agonist GC-1 (sobetirome) from a novel nanochannel membrane implant was assessed in an obese, pre-diabetic rhesus macaque. Dramatic loss of white adipose tissue in the abdomen from 36 to 18% was observed via magnetic resonance imaging in conjunction with normalized serum insulin and glycemia, with no signs of cardiotoxicity shown. The non-human primate study highlights sustained low-dose delivery of GC-1 from our minimally invasive subcutaneous implant as a valuable approach to induce weight loss and manage obesity and comorbidities, including type 2 diabetes.

Topics: Acetates; Animals; Drug Delivery Systems; Macaca mulatta; Nanotechnology; Obesity; Phenols

Our objective was to assess the sustained, low-dose and constant administration of the thyroid receptor-β (TRβ)-selective agonist GC-1 (sobetirome) from a novel nanochannel membrane device (NMD) for drug delivery. As it known to speed up metabolism, accomplish weight loss, improve cholesterol levels and possess anti-diabetic effects, GC-1 was steadily administered by our NMD, consisting of an implantable nanochannel membrane, as an alternative to conventional daily administration, which is subject to compliance issues in clinical settings.. Diet-induced obese C57BL/J6 male mice were fed a very high-fat diet (VHFD) and received NMD implants subcutaneously. Ten mice per group received capsules containing GC-1 or phosphate-buffered saline (control). Weight, lean and fat mass, as well as cholesterol, triglycerides, insulin and glucose, were monitored for 24 days. After treatment, plasma levels of thyroid-stimulating hormone (TSH) and thyroxine were compared. mRNA levels of a panel of thermogenic markers were examined using real-time PCR in white adipose tissue (WAT) and brown adipose tissue (BAT). Adipose tissue, liver and local inflammatory response to the implant were examined histologically. Pancreatic islet number and β-cell area were assessed.. GC-1 released from the NMD reversed VHFD-induced obesity and normalized serum cholesterol and glycemia. Significant reductions in body weight and fat mass were observed within 10 days, whereas reductions in serum cholesterol and glucose levels were seen within 7 days. The significant decrease in TSH was consistent with TRβ selectivity for GC-1. Levels of transcript for Ucp1 and thermogenic genes PGC1a, Cidea, Dio2 and Cox5a showed significant upregulation in WAT in NMD-GC-1-treated mice, but decreased in BAT. Although mice treated by NMD-GC-1 showed a similar number of pancreatic islets, they exhibited significant increase in β-cell area.. Our data demonstrate that the NMD implant achieves steady administration of GC-1, offering an effective and tightly controlled molecular delivery system for treatment of obesity and metabolic disease, thereby addressing compliance.

Topics: Acetates; Animals; Diet, High-Fat; Disease Models, Animal; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular Targeted Therapy; Obesity; Phenols; Thyroid Hormone Receptors beta

It is well known that thyroid hormone affects body composition; however, the effect of the thyroid hormone receptor beta (TRbeta)-selective thyromimetic GC-1 on this biological feature had not been demonstrated. In the current study, we compared the effects of a 6-week treatment with triiodothyronine (T3; daily injections of 3 or 6 microg/100 g body weight) or GC-1 (equimolar doses) on different metabolic parameters in adult female rats. Whereas all animals gained weight (17-25 g) in a way not basically affected by T3 or GC-1 treatment, only T3 treatment selectively increased food intake (50-70%). Oxygen consumption was significantly and equally increased (50-70%) by T3 and GC-1. Analysis of body composition by dual-energy X-ray absorptiometry (DEXA) revealed that, whereas control animals gained about 80% of fat mass, T3- or GC-1-treated animals lost 70-90 and approximately 20% respectively. Direct analysis of the carcass showed that T3 treatment promoted a 14-74% decrease in fat content but GC-1 treatment promoted only a 15-23% reduction. The gain in lean mass by DEXA and the carcass protein content were not affected by T3 or GC-1 treatment. However, the mass of individual skeletal muscles was negatively affected by T3 but only barely by GC-1. These findings highlight the potential use of GC-1 for the treatment of obesity and the metabolic syndrome.

Topics: Absorptiometry, Photon; Acetates; Adipose Tissue; Animals; Body Composition; Energy Metabolism; Female; Heart; Muscle, Skeletal; Obesity; Organ Size; Oxygen Consumption; Phenols; Random Allocation; Rats; Rats, Wistar; Thyroid Hormone Receptors beta; Triiodothyronine